My primary research goal is to identify molecular genetic factors informative about developmental behavioral disorders, including autism, schizophrenic, and major depression. As a clinician, I serve as Medical Director and Attending Psychiatrist at the Emory Autism Center, where I see adult patients with autism and related developmental disorders, as well as adults with known genetic/chromosomal abnormalities who require behavioral healthcare.
While family and twin studies provide strong support for genetic contributions to many common psychiatric disorders, the roles of individual genes in these disorders have been difficult to determine, probably because multiple genes interact with environmental and developmental influences to produce these disorders. Our lab has pursued analysis of endophenotypes as a strategy for reducing the complexity of genotype-phenotype relationships in behavioral disorders. Endophenotypes are traits that correlate or otherwise are relevant to a complex disorder, but which themselves more directly reflect the action of one or a few genes. A major focus of our research to date has been on plasma levels of dopamine ?-hydroxylase, the enzyme catalyzing conversion of dopamine to norepinephrine. Building on early linkage findings from other groups, we have shown that sequence variation at the DBH locus accounts for up to 50% of the variance in plasma D?H activity, and we have used this finding as a basis for investigation of psychosis in major depression and cocaine dependence.
As a new member of the Department of Human Genetics, and of Psychiatry and Behavioral Sciences, I hope to expand our work into other biochemical, physiological and psychological traits associated with psychiatric illness. For example, neurochemical markers of hypothalamic-pituitary-adrenal axis function represent excellent endophenotypes for investigation of how genes may modify expression of major depression, psychotic illness, post-traumatic stress disorder, and substance abuse. We are developing candidate-gene approaches for investigating such endophenotypes.
An additional interest of mine is understanding and treating psychiatric symptoms and syndromes associated with clearly defined genetic and chromosomal disorders such as the 22q11 deletion syndrome (in which 25-30% of adults with the syndrome meet criteria for schizophrenia). I am collaborating with colleagues in Human Genetics and Psychiatry and Behavioral Sciences to develop a multi-disciplinary clinic addressing the complex clinical needs of patients and families with 22q11DS.
Areas of Specialization / Research Interests
1. Biochemical genetics of serum dopamine -hydroxylase activity. This focus seeks to improve our understanding of how sequence variation at the DBH locus. Our main approach in humans is to conduct SNP-based association studies and resequencing analyses on DNA, and assay DH activity and protein levels in the serum. We are trying to get funding at present to expand this work into mouse models by “knocking in” human DBH constructs on a mouse Dbh -/- background.
2. Genetic pathways of risk for behavioral disorders in children born to women treated during pregnancy for mental illness. We are testing candidate-SNP hypotheses in samples of DNA from infants born to women treated in the Emory Women’s Mental Health Program (WMHP, Director, Zachary Stowe, MD). The infants are undergoing extensive evaluation during the first year of life, and we are working to secure funding for longer term longitudinal follow up of the cohort. Newer directions in this work include examination of DNA-methylation in order to investigate epigenetic mechanisms in child development.
3. Behavioral features and development in people with 22q11 Deletion Syndrome (22q11DS). This work focuses on understanding the nature of behavioral differences in people with interstitial deletions of 22q11.2 (frequency ~1:4000). Disorders associated with 22q11DS include autism-spectrum disorders, schizophrenia and mood disorders. Currently analyzing data gathered from adults with 22q11DS assessed with a variety of psychometic approaches.
4. Copy number variants (CNV) in schizophrenia: We are currently pursuing funding for a large-scale ascertainment of clinically diagnosed psychotic adults in order to investigate the role of copy number variants in schizophrenia-spectrum disorders.
B.A., Johns Hopkins University, 1980
M.D. and Ph.D. (Neuroscience), Albert Einstein College of Medicine, 1988
Psychiatric Residency, Columbia University/New York State Psychiatric Institute
Reviewer, Behavioral Genetics and Epidemiology Study Section (BGES), Center for Scientific Review, National Institutes of Health
American Society of Human Genetics
Society for Neuroscience
Society of Biological Psychiatry
American College of Neuropsychopharmacology